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Anus & perianal area

Premalignant

Squamous dysplasia

Authors: Irene Y. Chen, M.D., Xiaoyan Liao, M.D., Ph.D.

Editorial Board Members: Claudio Luchini, M.D., Ph.D., Naziheh Assarzadegan, M.D.

Last author update: 30 November 2022

Last staff update: 16 December 2024 (update in progress)

Copyright: 2002-2024, PathologyOutlines.com, Inc.

PubMed Search: Squamous dysplasia

Table of Contents

Cite this page: Chen IY, Liao X. Squamous dysplasia. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/anusdysplasia.html. Accessed December 26th, 2024.

Definition / general

Noninvasive neoplastic proliferation of the anal squamous epithelium with cytologic and architectural abnormalities
Associated with human papillomavirus (HPV) infection

Essential features

Often associated with human papillomavirus genotypes
- Low risk HPV mediates the development of low grade lesions
- High risk HPV mediates the development of high grade lesions
Most cases are incidental findings in asymptomatic patients
Immunocompromised patients are at increased risk
Progression to squamous cell carcinoma is influenced by immune status and smoking

Terminology

Squamous intraepithelial lesion (SIL)
Anal intraepithelial neoplasia (anal IEN / AIN)
Anal squamous intraepithelial neoplasia (ASIN)

ICD coding

ICD-O:
- 8077/0 - squamous intraepithelial neoplasia, low grade
- 8077/2 - squamous intraepithelial neoplasia, high grade
ICD-11:
- 2E92.5 & XH3Y37 - benign neoplasm of anus or anal canal & esophageal squamous intraepithelial neoplasia (dysplasia), low grade
- 2E61.2 & XH9ND8 - carcinoma in situ of anal canal & esophageal squamous intraepithelial neoplasia (dysplasia), high grade

Epidemiology

Rising incidence due to evolving sexual behavior and an increase in HPV infection rates
Immunodeficient (HIV and non-HIV immunosuppression) patients are at increased risk and present at a younger age
Additional risk factors: anoreceptive intercourse, coinfection with other sexually transmitted diseases and cigarette smoking (Papillomavirus Res 2017;4:90, Br J Cancer 2015;112:1568)
Incidence is higher in women and is unrelated to the prevalence of HIV, unlike in men

Sites

Anus: anal canal, usually the transitional zone
Also occurs in the perianal skin (< 5 cm to the anal verge / margin)

Pathophysiology

HPV associated oncoproteins:
- E6
  - Inactivates p53, allowing survival of cells with genotoxic damage
  - Inhibits p21, leading to loss of cyclin E / CDK2 inhibition and progression through the cell cycle
- E7
  - Inhibits RB1, leading to a continuous proliferation of mutation bearing cells
    - Loss of RB1 leads to overexpression of p16, which is used as a diagnostic surrogate marker
Reference: World J Gastrointest Oncol 2022;14:369

Etiology

Human papillomavirus (HPV) (Tumour Virus Res 2022;14:200239)
- Double stranded DNA virus of Papillomaviridae family
- Infects humans only
- More than 200 types
  - Low risk genotypes (6, 11, 42, 43, 44) associated with low grade lesions
    - HPV 6 and 11 are most common in > 90% of condyloma acuminatum
  - High risk genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) associated with high grade lesions and invasive squamous cell carcinoma
    - HPV 16 is most common in 28% of low grade and 68% of high grade lesions
  - > 1 serotype may be found in lesions
Subdivided based on tissue tropism (Cancer Epidemiol Biomarkers Prev 2008;17:1611):
- Anogenital
- Cutaneous
- Other mucosal sites
- Multicentricity is common; > 33% of women with anal HPV also have cervical HPV
Most are asymptomatic or resolve within 12 months (J Natl Cancer Inst 2008;100:513)
A small fraction persists or progresses to squamous dysplasia or squamous cell carcinoma

Clinical features

Often asymptomatic, some present with bleeding or pruritis
Most cases are incidental findings in benign minor surgical specimens such as hemorrhoids
May present as papules, plaques, polyps or mass lesions

Diagnosis

Anal exfoliative cytology
- Sensitivity and specificity for detecting high grade squamous dysplasia are 71% and 73%, respectively (Clin Infect Dis 2018;67:1262)
High resolution anoscopy with tissue biopsy is the gold standard (J Low Genit Tract Dis 2016;20:283)

Laboratory

See Molecular / cytogenetics description

Prognostic factors

Most LSIL will regress in immunocompetent patients (Arch Pathol Lab Med 2012;136:1266)
Recurrence rate of HSIL after wide local excision ranges between 9 - 63% (Dis Colon Rectum 2012;55:735)
- Recurrence rate is much higher in HIV patients
  - 53 - 67% recurrence rate over 18 - 24 months in HIV+ women and 24 - 53% in HIV+ men (J Acquir Immune Defic Syndr 2020;84:66, AIDS 2017;31:1245)
- May progress to squamous cell carcinoma

Case reports

43 year old man with HIV presented with persistent bloody stool (Int J Clin Exp Pathol 2014;7:3456)
55 year old woman was referred to colonoscopy because of constipation and hematochezia (ACG Case Rep J 2022;9:e00792)
65 year old woman was found to have a white flat lesion in contact with the dentate line on screening colonoscopy (Acta Gastroenterol Belg 2022;85:108)

Treatment

Treatment modalities vary by geographic location
- Fulguration with electrocautery during anoscopy
  - For lesions that are too large for the office based procedure
- Office based ablation techniques
  - Via infrared coagulation, hyfrecation, argon plasma coagulation or radiofrequency
- Topical therapy (Lancet Oncol 2013;14:346)
  - 5-fluorouracil (5FU)
  - Imiquimod
  - Trichloroacetic acid (TCA)
- HPV vaccination (N Engl J Med 2011;365:1576, Hum Vaccin Immunother 2016;12:1348)
  - Decreases the risk of recurrence in high grade lesions
  - Effective in anal cancer prevention when administered early
Posttreatment surveillance is required given the high rate of local recurrence
Reference: J Anus Rectum Colon 2022;6:92

Clinical images

Contributed by Xiaoyan Liao, M.D., Ph.D.

Condyloma acuminatum

Images hosted on other servers:

Anoscopy

Gross description

May present as papules, plaques or mass lesions
When present at the anal canal or dentate line, may be mistaken as rectal polyp

Microscopic (histologic) description

Diagnosis and grading of dysplasia is based on cellular atypia, degree of maturation and mitotic rate (Hum Pathol 2022 Jul 16 [Epub ahead of print])
- Mild dysplasia (AIN1, condyloma acuminatum)
  - Cytologic and architectural atypia involving the lower 33% of the epithelial thickness
    - Often shows koilocytic changes characterized as perinuclear cavitation and nuclear features of low grade squamous intraepithelial lesion, to include nuclear enlargement, coarse chromatin and irregular nuclear membranes (StatPearls: Koilocytosis [Accessed 4 November 2022])
      - Pathognomonic but not required for diagnosis
  - Condyloma acuminatum is exophytic, papillary growth of squamous lesion with parakeratosis and koilocytosis
- Moderate dysplasia (AIN2): cytologic and architectural atypia involving > 33% but < 66% of the epithelial thickness
  - Increased nuclear enlargement and coarse chromatin, compared to AIN1
  - Increased mitosis
- Severe dysplasia (AIN3): cytologic and architectural atypia involving > 66% of the epithelial thickness
  - Significant nuclear enlargement and atypia, high N:C ratios, increased mitosis with often atypical mitotic figures
  - Sometimes interchangeable with carcinoma in situ, which is full thickness squamous dysplasia without any maturation
Diagnostic terms are now unified under the lower anogenital squamous terminology (LAST) standardization project (Arch Pathol Lab Med 2012;136:1266)
- Low grade squamous intraepithelial lesion (LSIL)
  - Cytologic and architectural alteration involving < 33% of the epithelium
  - Includes lesions that were previously classified as mild dysplasia, anal IEN 1 (AIN1) and condyloma acuminatum
- High grade squamous intraepithelial lesion (HSIL)
  - Cytologic and architectural alteration involving > 33% of the epithelium
  - Includes lesions that were previously classified as moderate dysplasia, severe dysplasia, carcinoma in situ, Bowen disease and bowenoid papulosis

Microscopic (histologic) images

Contributed by Xiaoyan Liao, M.D., Ph.D. and @AnaPath10 on Twitter

Flat squamous proliferation

Papillary squamous proliferation

Papillary squamous proliferation, parakeratosis and koilocytosis

Condyloma with invasion

Invasive
squamous cell
carcinoma arising
in condyloma

High grade squamous intraepithelial lesion

HSIL

HSIL at the anal transitional zone

Involving a hemorrhoid

Squamous dysplasia

p16 immunohisto-
chemistry

HPV in situ hybridization

Squamous dysplasia

Cytology description

Can be categorized as LSIL, HSIL or atypical squamous cells of uncertain significance (ASCUS)
LSIL: hyperchromasia, nuclear irregularity, koilocytotic atypia and > 3 fold nuclear enlargement compared to superficial squamous cells
HSIL: small, immature appearing cells with markedly increased N:C ratio, coarse chromatin and irregular nuclear contour
ASCUS: typical cells that do not meet the criteria for LSIL or HSIL
Reference: Diagn Cytopathol 2010;38:538

Cytology images

Contributed by Irene Y. Chen, M.D.

Anal Pap smear

Images hosted on other servers:

LSIL

Positive stains

p16:
- Positive is defined as diffuse, strong, nuclear and cytoplasmic block-like staining
- Surrogate marker for high risk HPV infection
  - Distinguish HSIL from reactive change (91% sensitivity) (Am J Surg Pathol 2021;45:1573)
  - Distinguish AIN2 from AIN1 (89% sensitivity) (Am J Surg Pathol 2021;45:1573)
- Can be positive in LSIL / AIN1 (37%) (Am J Surg Pathol 2021;45:1573)
  - Morphology is still the key for diagnosis
  - p16 is not recommended when histologic diagnosis is clear cut
HPV immunostain: positive nuclear staining highlights virally infected cells
HPV RNA in situ hybridization
- Detect HPV E6 / E7 mRNA transcripts in both transcriptionally active state and formalin fixed paraffin embedded (FFPE)
- Positive staining with dot-like cytoplasmic and nuclear staining
- High sensitivity and specificity (Am J Surg Pathol 2017;41:607)
- More sensitive than HPV immunostain
HPV DNA in situ hybridization
- High specificity (89%) but lower sensitivity (83%)
Ki67: proliferation beyond the basal layer

Negative stains

p16: negative or weak and patchy in low grade lesions

Molecular / cytogenetics description

Polymerase chain reaction
- Quantitative reverse transcriptase PCR to detect HPV E6 / E7 mRNA
  - Considered the gold standard by the FDA
  - Limited utility due to exclusiveness to fresh frozen tissue
- Quantitative PCR to detect HPV DNA
  - Cannot distinguish transcriptionally active infection versus passenger
Reference: Infect Agent Cancer 2020;15:46

Sample pathology report

Anal canal, right lateral, biopsy:
- High grade squamous intraepithelial lesion (moderate dysplasia, AIN2)

Differential diagnosis

Inflammatory changes / repair:
- Superficial maturation and cellular polarity are maintained
- Round nuclei and may have prominent nucleoli
- No hyperchromasia
Radiation atypia:
- Cytomegaly and karyomegaly with the maintenance of a low N:C ratio
- Smudgy chromatin with prominent nucleoli
Squamous cell carcinoma:
- Foci of invasion
- Mass forming
- Adjacent area may show AIN as a precursor lesion

Additional references

WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

An anal lesion is excised from a 33 year old woman (see image above). No area of invasion is identified on histologic examination. Which of the following statements is true?

Immunocompromised patients are at increased risk and present at a younger age
Most cases are incidental findings in asymptomatic patients and do not recur after excision
Often associated with human papillomavirus genotype 6 and 11
p16 is often patchy in high grade lesions

Board review style answer #1

A. Immunocompromised patients (particularly those HIV+) are at increased risk and present at a younger age

Comment Here

Reference: Squamous dysplasia

Board review style question #2

Regarding human papillomavirus (HPV), which of the following is correct?

Diffuse p16 immunostaining positivity is a surrogate marker for both low and high risk HPV infection
High risk HPVs can be associated with low grade lesions
It is a single stranded RNA virus that does not insert into the human genome
It only infects the squamous epithelium

Board review style answer #2

B. High risk HPVs can be associated with low grade lesions. While high risk HPVs are usually associated with high grade dysplasia, they can be associated with low grade lesions.

Comment Here

Reference: Squamous dysplasia

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